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Abstract Background Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. Methods This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was β2-microglobulin removal rate (β2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. Results 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest β2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. Conclusions The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. Trial registration eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281).

While efficient removal of uremic toxins and accumulated water is pivotal for the well-being of dialysis patients, protein adsorption to the dialyzer membrane reduces the performance of a dialyzer. Hydrophilic membrane modification with polyvinylpyrrolidone (PVP) has been shown to reduce protein adsorption and to stabilize membrane permeability. In this study we compared middle molecule clearance and filtration performance of nine polysulfone-, polyethersulfone-, and cellulose-based dialyzers over time. Protein adsorption was simulated in recirculation experiments, while β2-microglobulin clearance as well as transmembrane pressure (TMP) and filtrate flow were determined over time. The results of this study showed that β2-microglobulin clearance (−7.2 mL/min/m2) and filtrate flow (−54.4 mL/min) decreased strongly during the first 30 min and slowly afterwards (−0.7 mL/min/m2 and −6.8 mL/min, respectively, for the next 30 min); the TMP increase (+37.2 mmHg and +8.6 mmHg, respectively) showed comparable kinetics. Across all tested dialyzers, the dialyzer with a hydrophilic modified membrane (FX CorAL) had the highest β2-microglobulin clearance after protein fouling and the most stable filtration characteristics. In conclusion, hydrophilic membrane modification with PVP stabilizes the removal capacity of middle molecules and filtration performance over time. Such dialyzers may have benefits during hemodiafiltration treatments which aim to achieve high exchange volumes.

Despite the significant medical and technical improvements in the field of dialytic renal replacement modalities, morbidity and mortality are excessively high among patients with end-stage kidney disease, and most interventional studies yielded disappointing results. Hemodiafiltration, a dialysis method that was implemented in clinics many years ago and that combines the two main principles of hemodialysis and hemofiltration—diffusion and convection—has had a positive impact on mortality rates, especially when delivered in a high-volume mode as a surrogate for a high convective dose. The achievement of high substitution volumes during dialysis treatments does not only depend on patient characteristics but also on the dialyzer (membrane) and the adequately equipped hemodiafiltration machine. The present review article summarizes the technical aspects of online hemodiafiltration and discusses present and ongoing clinical studies with regards to hard clinical and patient-reported outcomes.

The dialyzer is the core element in the hemodialysis treatment of patients with end-stage kidney disease (ESKD). During hemodialysis treatment, the dialyzer replaces the function of the kidney by removing small and middle-molecular weight uremic toxins, while retaining essential proteins. Meanwhile, a dialyzer should have the best possible hemocompatibility profile as the perpetuated contact of blood with artificial surfaces triggers complement activation, coagulation and immune cell activation, and even low-level activation repeated chronically over years may lead to undesired effects. During hemodialysis, the adsorption of plasma proteins to the dialyzer membrane leads to a formation of a secondary membrane, which can compromise both the uremic toxin removal and hemocompatibility of the dialyzer. Hydrophilic modifications of novel dialysis membranes have been shown to reduce protein adsorption, leading to better hemocompatibility profile and performance stability during dialysis treatments. This review article focuses on the importance of performance and hemocompatibility of dialysis membranes for the treatment of dialysis patients and summarizes recent studies on the impact of protein adsorption and hydrophilic modifications of membranes on these two core elements of a dialyzer.

CVD remains the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD profoundly affects HDL composition and functionality, but whether abnormal HDL independently contributes to cardiovascular events in CKD patients remains elusive. In the present study, we assessed whether compositional and functional properties of HDL predict cardiovascular outcome among 526 nondialysis CKD patients who participate in the CARE FOR HOMe study. We measured HDL cholesterol, the content of HDL-associated proinflammatory serum amyloid A (SAA), and activities of the HDL enzymes paraoxonase and lipoprotein-associated phospholipase A2 (Lp-PLA2). In addition, we assessed the antioxidative activity of apoB-depleted serum. During a mean follow-up of 5.1 ± 2.1 years, 153 patients reached the predefined primary endpoint, a composite of atherosclerotic cardiovascular events including cardiovascular mortality and death of any cause. In univariate Cox regression analyses, lower HDL-cholesterol levels, higher HDL-associated SAA content, and lower paraoxonase activity predicted cardiovascular outcome, while Lp-PLA2 activity and antioxidative capacity did not. HDL-cholesterol and HDL-paraoxonase activity lost their association with cardiovascular outcome after adjustment for traditional cardiovascular and renal risk factors, while SAA lost its association after further adjustment for C-reactive protein. In conclusion, our data suggest that neither HDL quantity nor HDL composition or function independently predict cardiovascular outcome among nondialysis CKD patients.

Abstract Background Application of genetically modified bone marrow concentrates in articular cartilage lesions is a promising approach to enhance cartilage repair by stimulating the chondrogenic differentiation processes in sites of injury. Method In the present study, we examined the potential benefits of transferring the proliferative and pro‐chondrogenic basic fibroblast growth factor (FGF‐2) to human bone marrow aspirates in vitro using the clinically adapted recombinant adeno‐associated virus (rAAV) vectors to monitor the biological and chondrogenic responses over time to the treatment compared with control (lacZ) gene application. Results Effective, significant FGF‐2 gene transfer and expression via rAAV was established in the aspirates relative to the lacZ condition (from ~ 97 to 36 pg rhFGF‐2/mg total proteins over an extended period of 21 days). Administration of the candidate FGF‐2 vector led to prolonged increases in cell proliferation, matrix synthesis, and chondrogenesis but also to hypertrophic and terminal differentiation in the aspirates. Conclusion The present evaluation shows the advantages of rAAV‐mediated FGF‐2 gene transfer to conveniently modify bone marrow concentrates as a future approach to directly treat articular cartilage lesions, provided that expression of the growth factor is tightly regulated to prevent premature hypertrophy in vivo.

BACKGROUND:Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. METHODS:Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. RESULTS:PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. CONCLUSION:In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.

Abstract Background Vascular calcification is a major contributor to the high cardiac burden among hemodialysis patients. A novel in vitro T50-test, which determines calcification propensity of human serum, may identify patients at high risk for cardiovascular (CV) disease and mortality. We evaluated whether T50 predicts mortality and hospitalizations among an unselected cohort of hemodialysis patients. Methods This prospective clinical study included 776 incident and prevalent hemodialysis patients from 8 dialysis centers in Spain. T50 and fetuin-A were determined at Calciscon AG, all other clinical data were retrieved from the European Clinical Database. After their baseline T50 measurement, patients were followed for two years for the occurrence of all-cause mortality, CV-related mortality, all-cause and CV-related hospitalizations. Outcome assessment was performed with proportional subdistribution hazards regression modelling. Results Patients who died during follow-up had a significantly lower T50 at baseline as compared to those who survived (269.6 vs. 287.7 min, p = 0.001). A cross-validated model (mean c statistic: 0.5767) identified T50 as a linear predictor of all-cause-mortality (subdistribution hazard ratio (per min): 0.9957, 95% CI [0.9933;0.9981]). T50 remained significant after inclusion of known predictors. There was no evidence for prediction of CV-related outcomes, but for all-cause hospitalizations (mean c statistic: 0.5284). Conclusion T50 was identified as an independent predictor of all-cause mortality among an unselected cohort of hemodialysis patients. However, the additional predictive value of T50 added to known mortality predictors was limited. Future studies are needed to assess the predictive value of T50 for CV-related events in unselected hemodialysis patients.

BackgroundAnemia is a major comorbidity of patients with end-stage renal disease and poses an enormous economic burden to health-care systems. High dose erythropoiesis-stimulating agents (ESAs) have been associated with unfavorable clinical outcomes. We explored whether mixed-dilution hemodiafiltration (Mixed-HDF), based on its innovative substitution modality, may improve anemia outcomes compared to the traditional post-dilution hemodiafiltration (Post-HDF).MethodsWe included 174 adult prevalent dialysis patients (87 on Mixed-HDF, 87 on Post-HDF) treated in 24 NephroCare dialysis centers between January 2010 and August 2016 into this retrospective cohort study. All patients were dialyzed three times per week and had fistula/graft as vascular access. Patients were matched at baseline and followed over a one-year period. The courses of hemoglobin levels (Hb) and monthly ESA consumption were compared between the two groups with linear mixed models.ResultsMean baseline Hb was 11.9±1.3 and 11.8±1.1g/dl in patients on Mixed- and Post-HDF, respectively. While Hb remained stable in patients on Mixed-HDF, it decreased slightly in patients on Post-HDF (at month 12: 11.8±1.2 vs 11.1±1.2g/dl). This tendency was confirmed by our linear mixed model (p = 0.0514 for treatment x time interaction). Baseline median ESA consumption was 6000 [Q1:0;Q3:16000] IU/4 weeks in both groups. Throughout the observation period ESA doses tended to be lower in the Mixed-HDF group (4000 [Q1:0;Q3:16000] vs 8000 [Q1:0;Q3:20000] IU/4 weeks at month 12; p = 0.0791 for treatment x time interaction). Sensitivity analyses, adjusting for differences not covered by matching at baseline, strengthened our results (Hb: p = 0.0124; ESA: p = 0.0687).ConclusionsResults of our explorative study suggest that patients on Mixed-HDF may have clinical benefits in terms of anemia management. This may also have a beneficial economic impact. Future studies are needed to confirm our hypothesis-generating results and to provide additional evidence on the potential beneficial effects of Mixed-HDF.